One measure of the potential usefulness of an oral dosage form of a new pharmaceutical agent is the bioavailability observed after oral administration of the dosage form. Various factors can affect the bioavailability of a drug when administered orally. These factors include aqueous solubility, drug absorption throughout the gastrointestinal tract, dosage strength and first: pass effect. Aqueous solubility is one of the most important of these factors. When a drug has poor aqueous solubility, attempts are often made to identify salts or other derivatives of the drug which have improved aqueous solubility. When a salt or other derivative of the drug is identified which has good aqueous solubility, it is generally accepted that an aqueous solution formulation of this salt or derivative will provide the optimum oral bioavailability. The bioavailability of the oral solution formulation of a drug is then generally used as the standard or ideal bioavailability against which other oral dosage forms are measured.
For a variety of reasons, such as patient compliance and taste masking, a solid dosage form, such as capsules, is usually preferred over a liquid dosage form. However, oral solid dosage forms of a drug generally provide a lower bioavailability than oral solutions of the drug. One goal of the development of a suitable capsule dosage form is to obtain a bioavailability of the drug that is as close as possible to the ideal bioavailability demonstrated by the oral solution formulation of the drug.
It has recently been determined that HIV protease inhibiting compounds are useful for inhibiting HIV protease in vitro and in vivo, are useful for inhibiting HIV (human immunodeficiency virus) infections and are useful for treating AIDS (acquired immunodeficiency syndrome). HIV protease inhibiting compounds typically are characterized by having poor oral bioavailability and there is a continuing need for the development of improved oral dosage forms for HIV protease inhibitors which have suitable oral bioavailability, stability and side effects profiles.
Examples of HIV protease inhibiting compounds include N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-(3-py ridylmethyl)-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-peritaneamide (i.e., indinavir) and related compounds, disclosed in European Patent Application No. EP541168, published May 12, 1993, and U.S. Pat. No. 5,413,999, issued May 9, 1995 which are both incorporated herein by reference; N-tert-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbon yl)-L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide (i.e., saquinavir) and related compounds, disclosed in U.S. Pat. No. 5,196,438, issued Mar. 23, 1993, which is incorporated herein by reference; 5(S)-Boc-amino-4(S)-hydroxy-6-phenyl-2( R)-phenylmethylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide and related compounds, disclosed in European Patent Application No. EP532466, published Mar. 17, 1993, which is incorporated herein by reference;
1-Naphthoxyacetyl-beta-methylthio-Ala-(2S,3S)-3-amino-2-hydroxy-4-butanoyl- 1,3-thiazolidine-4-t-butylamide (i.e., 1-Naphthoxyacetyl-Mta-(2S,3S)-AHPBA-Thz-NH-tBu), 5-isoquinolinoxyacetyl-beta-methylthio-Ala-(2S,3S)-3-amino-2-hydroxy-4-but anoyl-1,3-thiazolidine-4-t-butylamide (i.e., iQoa-Mta-Apns-Thz-NHtBu) and related compounds, disclosed in European Patent Application No. EP490667, published Jun. 17, 1992 and Chem. Pharm. Bull. 40 (8) 2251 (1992), which are both incorporated herein by reference; PA1 [1S-[1R*(R*),2S*]}-N.sup.1 [3-[[[(1,1-dimethylethyl)amino]carbonyl](2-methylpropyl)amino]-2-hydroxy-1 -(phenylmethyl)propyl]-2-[(2-quinolinylcarbonyl)amino]-butanediamide (i.e., SC-52151) and related compounds, disclosed in PCT Patent Application No. WO92/08701, published May 29, 1992 and PCT Patent Application No. WO93/2336, published Nov. 25, 1993, both of which are incorporated herein by reference; ##STR1## PA1 (a) an HIV protease inhibiting compound or a combination of HIV protease inhibiting compounds (preferably, a compound of the formula II or IV or saquinavir or nelfinavir or indinavir or VX-478, more preferably, a compound of the formula III or V or saquinavir or nelfinavir or indinavir or VX-478, or a combination of a compound of the formula II or nelfinavir and another HIV protease inhibitor (preferably, the compound of the formula IV or saquinavir or indinavir or nelfinavir or VX-478), or, more preferably, a combination of a compound of the formula III or nelfinavir and another HIV protease inhibitor (preferably, the compound of the formula V or saquinavir or indinavir or nelfinavir or VX-478)), PA1 (b) a pharmaceutically acceptable organic solvent which comprises a pharmaceutically acceptable long chain fatty acid or a mixture of a pharmaceutically acceptable long chain fatty acid and a pharmaceutically acceptable alcohol, and, optionally, PA1 (c) a pharmaceutically acceptable surfactant. PA1 (a) an HIV protease inhibiting compound or a combination of HIV protease inhibiting compounds (preferably, a compound of the formula II or IV or saquinavir or nelfinavir or indinavir or VX-478, more preferably, a compound of the formula III or V or saquinavir or nelfinavir or indinavir or VX-478, or a combination of a compound of the formula II or nelfinavir and another HIV protease inhibitor (preferably, the compound of the formula IV or saquinavir or indinavir or nelfinavir or VX-478), or, more preferably, a combination of a compound of the formula III or nelfinavir and another HIV protease inhibitor (preferably, the compound of the formula V or saquinavir or indinavir or nelfinavir or VX-478)), PA1 (b) a pharmaceutically acceptable organic solvent which comprises a pharmaceutically acceptable long chain fatty acid or a mixture of a pharmaceutically acceptable long chain fatty acid and a pharmaceutically acceptable alcohol, and, optionally, PA1 (c) a pharmaceutically acceptable surfactant, wherein the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule. PA1 (a) an HIV protease inhibiting compound or a combination of HIV protease inhibiting compounds (preferably, a compound of the formula II or IV or saquinavir or nelfinavir or indinavir or, more preferably, a compound of the formula III or V or saquinavir or nelfinavir or indinavir, or, most preferably, a compound of the formula III or V); or a combination of a compound of the formula II or nelfinavir and another HIV protease inhibitor (preferably, the compound of the formula IV or saquinavir or indinavir or nelfinavir, or, more preferably, a combination of a compound of the formula III or nelfinavir and another HIV protease inhibitor (preferably, the compound of the formula V or saquinavir or indinavir or nelfinavir), or, most preferably, a combination of a compound of formula III and a compound of formula V) in the amount of from about 1% to about 50% (preferably, from about 1% to about 40%; more preferably, from about 10% to about 40%; most preferably, from about 15% to about 40%) by weight of the total solution, PA1 (b) a pharmaceutically acceptable organic solvent which comprises (i) a pharmaceutically acceptable long chain fatty acid in the amount of from about 20% to about 99% (preferably, from about 30% to about 70%; more preferably, from about 40% to about 60%) by weight of the total solution or (ii) a mixture of (1) a pharmaceutically acceptable long chain fatty acid in the amount of from about 20% to about 99% (preferably, from about 30% to about 70%; more preferably, from about 40% to about 60%) by weight of the total solution and (2) a pharmaceutically acceptable alcohol in the amount of from about 0% to about 15% (preferably, from about 6% to about 12%) by weight of the total solution and PA1 (c) a pharmaceutically acceptable surfactant in the amount of from about 0% to about 40% (preferably, from about 2% to about 20% and most preferably, from about 5% to about 15%) by weight of the total solution. In a preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule. PA1 (a) ritonavir in the amount of from about 1% to about 30% (preferably, from about 5% to about 25%) by weight of the total solution, PA1 (b) a pharmaceutically acceptable organic solvent which comprises (i) a pharmaceutically acceptable long chain fatty acid in the amount of from about 40% to about 99% (preferably, from about 30% to about 70%; more preferably, from about 40% to about 60%) by weight of the total solution or (ii) a mixture of (1) a pharmaceutically acceptable long chain fatty acid in the amount of from about 40% to about 99% (preferably, from about 030% to about 70%; more preferably, from about 40% to about 60%) by weight of the total solution and (2) a pharmaceutically acceptable alcohol in the amount of from about 0% to about 15% (preferably, from about 6% to about 12%) by weight of the total solution and PA1 (c) a pharmaceutically acceptable surfactant in the amount of from about 0% to about 20% (preferably, from about 5% to about 10%) by weight of the total solution. In a more preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule. PA1 (a) ritonavir in the amount of from about 1% to about 30% (preferably, from about 5% to about 25%) by weight of the total solution, PA1 (b) a pharmaceutically acceptable organic solvent which comprises (i) oleic acid in the amount of from about 15% to about 99% (preferably, from about 30% to about 70%; more preferably, from about 40% to about 60%) by weight of the total solution or (ii) a mixture of (1) oleic acid in the amount of from about 15% to about 99% (preferably, from about 30% to about 70%; more preferably, from about 40% to about 60%) by weight of the total solution and (2) ethanol in the amount of from about 0% to about 12% (preferably, from about 10% to about 12%) by weight of the total solution or propylene glycol in the amount of from about 0% to about 10% (preferably, from about 5% to about 10%) by weight of the total solution or a mixture thereof in the amount of from about 0% to about 15% (preferably, from about 10% to about 15%) by weight of the total solution and PA1 (c) polyoxyl 35 castor oil in the amount of from about 0% to about 20% (preferably, from about 5% to about 10%) by weight of the total solution. In an even more preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule. PA1 (a) ritonavir in the amount of about 20% by weight of the total solution, PA1 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of from about 62% to about 64% by weight of the total solution and (2) ethanol in the amount of from about 10% to about 12%, preferably, about 12%, by weight of the total solution and PA1 (c) polyoxyl 35 castor oil in the amount of about 6% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of about 0.05% by weight of the total solution. PA1 (a) ritonavir in the amount of about 20% by weight of the total solution, PA1 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of about 65% by weight of the total solution and (2) ethanol in the amount of about 10% by weight of the total solution and PA1 (c) polyoxyl 35 castor oil in the amount of about 5% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.01% to about 0.05% by weight of the total solution). PA1 (a) ritonavir in the amount of about 20% by weight of the total solution, PA1 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of about 60% by weight of the total solution and (2) ethanol in the amount of about 10% by weight of the total solution and PA1 (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.01% to about 0.05% by weight of the total solution). PA1 (a) ritonavir in the amount of about 20% by weight of the total solution, PA1 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of about 70% by weight of the total solution and (2) a mixture of ethanol in the amount of about 5% by weight of the total solution and propylene glycol in the amount of about 5% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.01% to about 0.05% by weight of the total solution). PA1 (a) (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-[2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methyl butanoyl]amino-1,6-diphenylhexane in the amount of from about 1% to about 50% (preferably, from about 5% to about 35%) by weight of the total solution, PA1 (b) a pharmaceutically acceptable organic solvent which comprises (i) a pharmaceutically acceptable long chain fatty acid in the amount of from about 20% to about 99% (preferably, from about 30% to about 70%; more preferably, from about 40% to about 65%) by weight of the total solution or (ii) a mixture of (1) a pharmaceutically acceptable long chain fatty acid in the amount of from about 20% to about 99% (preferably, from about 30% to about 70%; more preferably, from about 40% to about 65%) by weight of the total solution and (2) a pharmaceutically acceptable alcohol in the amount of from about 0% to about 15% (preferably, from about 6% to about 12%) by weight of the total solution and PA1 (c) a pharmaceutically acceptable surfactant in the amount of from about 0% to about 40% (preferably, from about 2% to about 20% and preferably, from about 5% to about 15%) by weight of the total solution. In a more preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule. PA1 (a) (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-[2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methyl butanoyl]amino-1,6-diphenylhexane in the amount of from about 1% to about 50% (preferably, from about 5% to about 35%) by weight of the total solution, PA1 (b) a pharmaceutically acceptable organic solvent which comprises (i) oleic acid in the amount of from about 20% to about 99% (preferably, from about 30% to about 70%; more preferably, from about 40% to about 65%) by weight of the total solution or (ii) a mixture of (1) oleic acid in the amount of from about 20% to about 99% (preferably, from about 30% to about 70%; more preferably, from about 40% to about 65%) by weight of the total solution and (2) ethanol in the amount of from about 0% to about 12% (preferably, from about 10% to about 12%) by weight of the total solution or propylene glycol in the amount of from about 0% to about 10% (preferably, from about 5% to about 10%) by weight of the total solution or a mixture thereof in the amount of from about 0% to about 15% (preferably from about 5% to about 15%, most preferably, about 10%) by weight of the total solution and PA1 (c) polyoxyl 35 castor oil in the amount of from about 0% to about 20% (preferably, from about 5% to about 10%) by weight of the total solution. In an even more preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule. PA1 (a) (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-[2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methyl butanoyl]amino-1,6-diphenylhexane in the amount of about 30% by weight of the total solution, PA1 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of about 50% by weight of the total solution and (2) ethanol in the amount of about 10% by weight of the total solution and PA1 (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.01% to about 0.05% by weight of the total solution). PA1 (a) a mixture of ritonavir in the amount of from about 1% to about 30% (preferably, from about 5% to about 25%) by weight of the total solution and another HIV protease inhibitor in the amount of from about 1% to about 50% (preferably, from about 5% to about 40%) by weight of the total solution, PA1 (b) a pharmaceutically acceptable organic solvent which comprises (i) a pharmaceutically acceptable long chain fatty acid in the amount of from about 10% to about 98% (preferably, from about 30% to about 70%; more preferably, from about 40% to about 65%) by weight of the total solution or (ii) a mixture of (1) a pharmaceutically acceptable long chain fatty acid in the amount of from about 20% to about 98% (preferably, from about 30% to about 70%; more preferably, from about 40% to about 65%) by weight of the total solution and (2) a pharmaceutically acceptable alcohol in the amount of from about 0% to about 15% (preferably, from about 6% to about 12%) by weight of the total solution and PA1 (c) a pharmaceutically acceptable surfactant in the amount of from about 0% to about 20% (preferably, from about 5% to about 10%) by weight of the total solution. In a more preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule. PA1 (a) a mixture of ritonavir in the amount of from about 1% to about 30% (preferably, from about 5% to about 25%) by weight of the total solution and another HIV protease inhibitor in the amount of from about 1% to about 50% (preferably, from about 5% to about 40%) by weight of the total solution, PA1 (b) a pharmaceutically acceptable organic solvent which comprises (i) oleic acid in the amount of from about 10% to about 98% (preferably, from about 30% to about 70%; more preferably, from about 40% to about 65%) by weight of the total solution or (ii) a mixture of (1) oleic acid in the amount or from about 10% to about 98% (preferably, from about 30% to about 70%; more preferably, from about 40% to about 65%) by weight of the total solution and (2) ethanol in the amount of from about 0% to about 12% (preferably, from about 10% to about 12%) by weight of the total solution or propylene glycol in the amount of from about 0% to about 10% (preferably, from about 5% to about 10%) by weight of the total solution or a mixture thereof in the amount of from about 0% to about 15% (preferably, from about 10% to about 15%) by weight of the total solution and PA1 (c) polyoxyl 35 castor oil in the amount of from about 0% to about 20% (preferably, from about 5% to about 10%) by weight of the total solution. In an even more preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule. PA1 (a) a mixture of ritonavir in the amount of from about 1% to about 30% (preferably, from about 5% to about 25%) by weight of the total solution and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-[2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methyl butanoyl]amino-1,6-diphenylhexane in the amount of from about 1% to about 50% (preferably, from about 5% to about 40%) by weight of the total solution, PA1 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of from about 10% to about 88% (preferably, from about 40% to about 65%) by weight of the total solution and (2) ethanol in the amount of about 10% by weight of the total solution and PA1 (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.01% to about 0.05% by weight of the total solution). PA1 (a) a mixture of ritonavir in the amount of from about 1% to about 30% (preferably, from about 5% to about 25%) by weight of the total solution and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-[2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methyl butanoyl]amino-1,6-diphenylhexane in the amount of from about 1% to about 50% (preferably, from about 5% to about 40%) by weight of the total solution, PA1 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of from about 10% to about 88% (preferably, from about 40% to about 65%) by weight of the total solution and (2) propylene glycol in the amount of from about 5% to about 10% (preferably, from about 6% to about 8%) by weight of the total solution and PA1 (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.01% to about 0 05% by weight of the total solution). PA1 (a) a mixture of ritonavir in the amount of about 5% by weight of the total solution and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-[2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methyl butanoyl]amino-1,6-diphenylhexane in the amount of about 30% by weight of the total solution, PA1 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of about 45% by weight of the total solution and (2) ethanol in the amount of about 10% by weight of the total solution and PA1 (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.03% to about 0.05% by weight of the total solution). PA1 (a) a mixture of ritonavir in the amount of about 15% by weight of the total solution and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-[2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methyl butanoyl]amino 1,6-diphenylhexane in the amount of about 15% by weight of the total solution, PA1 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of about 50% by weight of the total solution and (2) ethanol in the amount of about 10% by weight of the total solution and PA1 (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.03% to about 0.05% by weight of the total solution). PA1 (a) a mixture of ritonavir in the amount of about 15% by weight of the total solution and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-[2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl]amino-1,6-diphenylhexane in the amount of about 5% by weight of the total solution, PA1 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of about 60% by weight of the total solution and (2) ethanol in the amount of about 10% by weight of the total solution and PA1 (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.03% to about 0.05% by weight of the total solution). PA1 (a) a mixture of ritonavir in the amount of about 10% by weight of the total solution and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-[2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methyl butanoyl]amino-1,6-diphenylhexane in the amount of about 20% by weight of the total solution, PA1 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of about 50% by weight of the total solution and (2) ethanol in the amount of about 10% by weight of the total solution and PA1 (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.03% to about 0.05% by weight of the total solution). PA1 (a) a mixture of ritonavir in the amount of about 13% by weight of the total solution and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-[2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methyl butanoyl]amino-1,6-diphenylhexane in the amount of about 17% by weight of the total solution, PA1 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of about 50% by weight of the total solution and (2) ethanol in the amount of about 10% by weight of the total solution and PA1 (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.03% to about 0.05% by weight of the total solution). PA1 (a) a mixture of ritonavir in the amount of about 6.0% by weight of the total solution and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-[2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methyl butanoyl]amino-1,6-diphenylhexane in the amount of about 24% by weight of the total solution, PA1 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of about 52.5% by weight of the total solution and (2) propylene glycol in the amount of about 7.5% by weight of the total solution and PA1 (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.01% to about 0.05% by weight of the total solution). PA1 (b) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution, in a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of about 52.5% by weight of the total solution and (2) propylene glycol in the amount of about 7.5% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.01% to about 0.05% by weight of the total solution). PA1 (a) a mixture of ritonavir in the amount of about 8% by weight of the total solution and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-[2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methyl butanoyl]amino-1,6-diphenylhexane in the amount of about 24% by weight of the total solution, PA1 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of about 50.5% by weight of the total solution and (2) propylene glycol in the amount of about 7.5% by weight of the total solution and PA1 (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.01% to about 0.05% by weight of the total solution). PA1 (a) a mixture of ritonavir in the amount of about 8.25% by weight of the total solution and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-[2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methyl butanoyl]amino-1,6-diphenylhexane in the amount of about 22% by weight of the total solution, PA1 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of about 52.25% by weight of the total solution and (2) propylene glycol in the amount of about 7.5% by weight of the total solution and PA1 (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.01% to about 0.05% by weight of the total solution). PA1 (a) a mixture of ritonavir in the amount of about 5% by weight of the total solution and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-[2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methyl butanoyl]amino-1,6-diphenylhexane in the amount of about 30% by weight of the total solution, PA1 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of about 47.5% by weight of the total solution and (2) propylene glycol in the amount of about 7.5% by weight of the total solution and PA1 (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.01% to about 0.05% by weight of the total solution). PA1 (a) a mixture of ritonavir in the amount of about 13% by weight of the total solution and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-[2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methyl butanoyl]amino 1,6-diphenylhexane in the amount of about 17% by weight of the total solution, PA1 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of about 52.5% by weight of the total solution and (2) propylene glycol in the amount of about 7.5% by weight of the total solution and PA1 (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.01% to about 0.05% by weight of the total solution). PA1 (a) a mixture of ritonavir in the amount of about 15% by weight of the total solution and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-[2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methyl butanoyl]amino-1,6-diphenylhexane in the amount of about 15% by weight of the total solution, PA1 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of about 52.5% by weight of the total solution and (2) propylene glycol in the amount of about 7.5% by weight of the total solution and PA1 (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.01% to about 0 05% by weight of the total solution). PA1 (a) a mixture of ritonavir in the amount of about 10% by weight of the total solution and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-[2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methyl butanoyl]amino-1,6-diphenylhexane in the amount of about 20% by weight of the total solution, PA1 (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of about 52.5% by weight of the total solution and (2) propylene glycol in the amount of about 7.5% by weight of the total solution and PA1 (c) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.01% to about 0.05% by weight of the total solution).
(i.e., VX-478) and related compounds, disclosed in PCT Patent Application No. WO94/05639, published Mar. 17, 1994, which is incorporated herein by reference; ##STR2##
and related compounds, disclosed in PCT Patent Application No. WO93/07128, published Apr. 15, 1993, which is incorporated herein by reference; ##STR3##
disclosed in PCT Patent Application No. WO95/09843, published Apr. 13, 1995 and U.S. Pat. No. 5,484,926, issued Jan. 16,1996, which are both incorporated herein by reference; ##STR4##
disclosed in European Patent Application No. EP580402, published Jan. 26, 1994, which is incorporated herein by reference; ##STR5##
and related compounds disclosed in PCT Patent Application No. WO 9506061, published Mar. 2, 1995, which is incorporated herein by reference and at 2nd National Conference on Human Retroviruses and Related Infections, (Washington, D.C., Jan. 29-Feb. 2, 1995), Session 88; and ##STR6##
(i.e., BILA 1096 BS) and related compounds disclosed in European Patent Application No. EP560268, published Sep. 15, 1993, which is incorporated herein by reference; and ##STR7##
compounds disclosed in PCT Patent Application No. WO 9530670, published Nov. 16, 1995, which is incorporated herein by reference; or a pharmaceutically acceptable salt of any of the above.
Other examples of HIV protease inhibiting compounds include compounds of the formula I: ##STR8##
wherein R.sub.1 is lower alkyl and R.sub.2 and R.sub.3 are phenyl and related compounds or a pharmaceutically acceptable salt thereof, disclosed in PCT Patent Application No. WO94114436, published Jul. 7, 1994 and U.S. Pat. No. 5,541,206, issued Jul. 30, 1996, both of which are incorporated herein by reference. The compounds of formula I are useful to inhibit HIV infections and, thus, are useful for the treatment of AIDS.
In particular, the compound of formula II, has been found to be especially effective as an inhibitor of HIV protease. ##STR9##
The most preferred compound of formula II is (2S,3S,: 5S)-5-(N-(N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)-amino)carbonyl) valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hyd roxyhexane (ritonavir; compound III) or a pharmaceutically acceptable salt thereof.
Other examples of HIV protease inhibiting compounds also include compounds of the formula IV: ##STR10##
wherein R.sub.1 is benzyl, R.sub.2 is benzyl or loweralkyl, R.sub.3 is loweralkyl and R.sub.5 is ##STR11##
and related compounds or a pharmaceutically acceptable salt thereof, disclosed in U.S. patent application Ser. No. 08/572,226, filed Dec. 13, 1996 and U.S. patent application Ser. No. 08/753,201, filed Nov. 21, 1996 and International Patent Application No. WO97/21685, published Jun. 19, 1997, all of which are incorporated herein by reference.
A preferred compound is the compound of formula IV wherein R.sub.1 and R.sub.2 are benzyl, R.sub.3 is isopropyl and R.sub.5 is ##STR12##
A most preferred compound of the formula IV is (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-[2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methyl butanoyl]amino-1,6-diphenylhexane (compound V) or a pharmaceutically acceptable salt thereof. The preparation of compound V is disclosed in U.S. patent application Ser. No. 08/572,226, filed Dec. 13,1996 and U.S. patent application Ser. No. 08/753,201, filed Nov. 21, 1996 and International Patent Application No. WO97/21685, published Jun. 19, 1997.
Compound III has an aqueous solubility of approximately 6 micrograms per milliliter at pH&gt;2. This is considered to be extremely poor aqueous solubility and, therefore, compound III in the free base form would be expected to provide very low oral bioavailability. In fact, the free base form of compound III, administered as an unformulated solid in a capsule dosage form, is characterized by a bioavailability of less than 2% following a 5 mg/kg oral dose in dogs.
Acid addition salts of compound III (for example, bis-hydrochloride, bis-tosylate, bis-methane sulfonate and the like) have aqueous solubilities of &lt;0.1 milligrams/milliliter. This is only a slight improvement over the solubility of the free base. This low aqueous solubility would not make practical the administration of therapeutic amounts of an acid addition salt of compound III as an aqueous solution. Furthermore, in view of this low aqueous solubility, it is not surprising that the bis-tosylate of compound III, administered as an unformulated solid in a capsule dosage form, is characterized by a bioavailability of less than 2% following a 5 mg/kg oral dose in dogs.
In order to have a suitable oral dosage form of compound III, the oral bioavailability of compound III should be at least 20%. Preferably, the oral bioavailability of compound III from the dosage form should be greater than about 40% and, more preferably, greater than about 50%.
While some drugs would be expected to have good solubility in organic solvents, it would not necessarily follow that oral administration of such a solution would give good bioavailability for the drug. It has been found that compound III has good solubility in pharmaceutically acceptable organic solvents and that the solubility in such solvents is enhanced in the presence of a pharmaceutically acceptable long chain fatty acid. Administration of the solution as an encapsulated dosage form (soft elastic capsules or hard gelatin capsules) provides an oral bioavailability of as high as about 60% or more.